Stability of pharmaceuticals is an ongoing concern. Of great concern to the Food and Drug Administration (FDA), moreover, is oxidative stability of active pharmaceutical ingredients (APIs). The reason that the FDA is so concerned is because oxidative stability can adversely affect the bioavailability of an API, for example, by decreasing or increasing bioavailability of the API from bodily absorption, and may potentially produce new material(s) that could be toxic.
In the last twenty years, there has been a shift in mindset in the pharmaceutical industry. Thus, for example, for many years, the industry shied away from semi-crystalline APIs owing to concerns about the stability of their amorphous content since, in some cases, an API compound may form different polymorphs, each of which has a different level of stability generally related to its energy state, and, with temperature and time, the API may convert between polymorphs, which can affect bioavailability. Generally, if given enough time, such polymorphic substances settle at the lowest ground state polymorph form. Be that as it may, owing to the number of new experimental drug candidates having poor water solubility and thus, in general, low bioavailability, the industry has developed technology intended to help stabilize these types of materials. Typically this is done by blending the API with an excipient such as a polymer generally recognized as safe, i.e., a GRAS approved polymer, which stabilizes the polymorph; or by producing the polymorph in the presence of a stabilizing polymer. These substances need testing to help verify that they are safe and effective.
Accordingly, the testing of pharmaceuticals and pharmaceutical candidates is critical. The most common way for evaluation oxidative stability of an API is to place it in an open vial in an oven, heat it at a set temperature, for example, about 40° C., 50° C., 60° C. or 80° C., and periodically remove samples from the vial for high pressure liquid chromatography (HPLC) analysis. Another common way for evaluation API oxidative stability is to add a small amount 35% hydrogen peroxide directly to the sample with API in an open vial, and, as above, place it in an oven, apply heat, and periodically remove samples for HPLC analysis. Both of these procedures are time consuming. For an oxidatively stable API, it can take months to show an appreciable amount of oxidation.
As necessary as oxidative stability testing of new APIs is to the pharmaceutical industry, however, specific, reliable protocols for the same appear to be lacking, yet still needed. Note, ICH Harmonised Tripartite Guidelines, “Stability Testing of New Drug Substances and Products, Q1A(R2),” Step 4 version dated 6 Feb. 2003; “Validation of Analytical Procedures: Text and Methodology Q2(R1),” Step 4 version parent guideline dated 27 Oct. 1994 (complementary guideline on methodology dated 6 Nov. 1996 incorporated in November 2005); United States Pharmacopeial Convention, USP 39, Aug. 1, 2016, General Chapters 1225 and 1226, “Validation of Compendial Procedures,” pages 1640-1645, and “Verification of Compendial Procedures,” page 1646; and Blessy et al., J. Pharm. Anal., 2014; 4(3): 159-165, “Development of forced degradation and stability indicating studies of drugs—a review.”
It would be desirable to improve upon the art; to ameliorate if not solve problem(s) in it, to include as aforesaid; and particularly to enhance oxidation testing of APIs and reduce the time and increase the reliability of such testing. It would be desirable to provide the art an alternative.